Salt-Inducing Assembly Polymorphism Strategy for Cytotoxicity Differentiation of Phenol-Soluble Modulin α3 Assemblies

Qize Xuan, Jiaxin He, Wenxue Zhang, Wei Zhang, Qi Zhang, Yao Zhou, Anqi Wei, Hao Wang, Hui Li, Chao Chen, Ping Wang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Phenol-soluble modulin α3 (PSMα3) can self-assemble into fibrous assemblies with a unique "cross-α" sheet structure, which serves as a key virulence factor in the infection of Staphylococcus aureus. However, the structure-cytotoxicity relationships of PSMα3 still remain elusive. Herein, we utilized the strategy of salt-inducing assembly polymorphism to controllably prepare three PSMα3 assemblies with morphological and structural distinctions, including amorphous aggregates (AAs), rigid fibrils (RFs), and oligomers/curvilinear fibrils (OCFs), which provided a convincing method to facilitate the structure-cytotoxicity investigation of PSMα3 assemblies. Our results affirmed that amyloid fibrillation was essential for the enhancement of PSMα3 cytotoxicity, which was proved based on the evidence that RFs and OCFs both triggered more obvious cytotoxicity than AAs. Furthermore, our study also demonstrated that the cytotoxicity was severely dependent on the size and structure of PSMα3 fibrils. In detail, smaller OCFs rich in α-helices exhibited stronger virulence than RFs with larger sizes and low α-helical contents. The cytotoxicity caused by such fibrils was achieved via a membrane-disrupting mechanism, in which RFs and OCFs might be prone to membrane thinning and perforation, respectively. This strategy of salt-inducing PSMα3 assembly polymorphism facilitated the comprehension of the relationship between the characteristics of PSMα3 assemblies and their cytotoxicity and was also helpful to understanding the intrinsic assembly mechanism of the PSMα3.

Original languageEnglish (US)
Pages (from-to)3318-3328
Number of pages11
JournalBiomacromolecules
Volume23
Issue number8
DOIs
StatePublished - Aug 8 2022

Bibliographical note

Funding Information:
This work was sponsored by the National Natural Science Foundation of China (nos. 21908059 and 21636003), the China Postdoctoral Science Foundation (no. 2019M651419), the Shanghai Sailing Program (nos. 19YF1410900 and 21YF1451700), the Natural Science Foundation of Shanghai (22ZR1415400), the Fundamental Research Funds for the Central Universities (no. 22221818014), the Shanghai Postdoctoral Excellence Program (no. 2018011), the Foundation of State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Sciences (grant no: GZKF202031), and the Open Funding Project of the State Key Laboratory of Bioreactor Engineering.

Funding Information:
The authors acknowledge the help from assistant professor Yibing Wang (East China University of Science and Technology) in the guidance of data analysis. The authors thank the Research Centre of Analysis and Test of East China University of Science and Technology for the sample characterization. The authors also thank the support from the Zhang Jiangshu Excellent Doctoral Program of East China University of Science and Technology.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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